Antimicrobial Therapy of Sinusitis

The medical management of acute bacterial sinusitis includes the use of antibiotics and adjuvant therapy

The variety of organisms involved in sinusitis, increasing levels of resistance to antibiotic agents, and the phenomenon of beta-lactamase “shielding” from antibiotic agents all contribute to the therapeutic challenges associated with the management of acute and chronic bacterial sinusitis. Even the proper selection of antimicrobials can be associated with failure to eradicate the infection because of local factors.

Local Factors Enabling Organisms to Survive Antimicrobial Therapy

• Inadequate penetration of antimicrobial agents
• A high protein concentration (can bind antimicrobial agents that have high protein binding)
• A high content of antimicrobial-inactivating enzymes (e.g., beta-lactamase)
• Decreased multiplication rate of organisms (interferes with the activity of bacteriostatic agents)
• Reduction in pH and oxygen partial pressure (reduces the efficacy of aminoglycosides and quinolones)
• Impairment of local defenses (e.g., phagocytosis, ciliary motility) or the sinus environment

Spontaneous recovery occurs in about 40-50% of patients. Despite this, appropriate antimicrobial therapy is beneficial and effective in facilitating the recovery and preventing suppurative complications.
The antimicrobial agents most commonly used to treat acute bacterial sinusitis include amoxicillin (with and without clavulanic acid), oral and parenteral cephalosporins, macrolides, trimethoprim-sulfamethoxazole (TMP-SMX), and the “new” quinolones (i.e. levofloxacin, and moxifloxacin).

Antibiotics used for bacterial sinusitis (PO)

Antibiotic

Adult dosage

Pediatric dosage (mg/kg)

Duration of therapy for acute sinusitis

(days)

Beta-lactams

Cefprozil (Cefzil)

250–500 mg bid

7.5–15 bid

10

Cefuroxime axetil (Ceftin)

250–500 mg bid

10–15 bid

10

Cefpodoxime (Vantin)

200–400 mg bid

5 bid

10

Cefdinir (Omnicef)

300 mg bid

7 bid/14 qd

10

Amoxicillin (Amoxil,Trimox,Wymox)

500 mg tid or 875 mg bid

20–45 bid

14

Amoxicillin-clavulanate (Augmentin)

500 mg tid* or 875 mg or 2000 mg (XR) bid*

22.5 or 45 (ES600) bid

10

Macrolides

Azithromycin (Zithromax)

250 mg qd

10 day 1, then 5 qd

3 or 5

Clarithromycin (Biaxin)

500 mg bid

7.5 bid

14

Fluoroquinolones

Levofloxacin (Levaquin)

500 mg qd

NA

10

Moxifloxacin (Avelox)

400 mg qd

NA

10

Others

Clindamycin (Cleocin)

150–450 mg tid or qid

7.5 qid or 6 tid

10

TMP-SMX (Bactrim, Septra)

160 mg/800 mg bid

8–12 bid

10

*Based on amoxicillin component.

NA = not approved for patients < 18 years of age.

In vitro efficacy of antimicrobial agents used in bacterial sinusitis therapy

Amoxicillin
• It has a well-known safety profile and is inexpensive.
• It is the most active of all the oral beta-lactams against susceptible pneumococci.
• Resistance to penicillin in S. pneumoniae isolates is relative and intermediate resistance may be overcome in most cases by using a higher doses of amoxicillin.
• An increase of 3 to 3.5 times the daily amount of amoxicillin is given to patients to overcome intermediate S. pneumoniae resistance.

Amoxicillin + clavulanate
• The addition of clavulanic acid (a beta-lactamase inhibitor) to amoxicillin enhances its efficacy against aerobic and anaerobic BLPB.
• Doubling the dose of amoxicillin while keeping the amount of clavulanate constant achieves efficacy against penicillin-resistant S. pneumoniae. A new formulation that delivers a high concentration of amoxicillin while keeping the amount of clavulanate unchanged is now available for children and adults, pharmacokinetically enhanced formulation of amoxicillin/clavulanate specifically designed to cover resistant S. pneumoniae with MIC of 2 or 4 mcg/mL. The formulation for children is 90 mg/kg/d of amoxicillin (given bid); clavulanate-to-amoxicillin ratio is 1:14. The adult formulation dispenses two bilayered tablets of 1000 mg amoxicillin and 62.5 mg clavulanate each (administered bid); clavulanate-to-amoxicillin ratio is 1:16.
• The first-line use of amoxicillin/clavulanate should be considered in patients with moderate-to-severe infections, and those with risk factors prompting a need for more effective antimicrobials.

Cephalosporins
• First-generation cephalosporins lack sufficient efficacy against H. influenzae, M. catarrhalis, and many S. pneumoniae strains.
• Some of the second-generation cephalosporins (cefdinir, cefuroxime axetil, and cefpodoxime proxetil) are active against penicillin-resistant Haemophilus and Moraxella spp.
• Some of the second-generation cephalosporins (cefprozil and cefuroxime axetil) are active against intermediately penicillin-resistant S. pneumoniae.
• Cefaclor and loracarbef are less effective than the other second-generation cephalosporins against penicillin-resistant S. pneumoniae, and Haemophilus and Moraxella spp.
• Third-generation cephalosporins (cefixime and ceftibuten) are mostly effective against H. influenzae and Moraxella spp., but are not effective against penicillin-resistant S. pneumoniae and S. aureus.
• Parenteral third-generation cephalosporins (cefotaxime or ceftriaxone) are effective against H. influenzae and M. catarrhalis that produce beta-lactamase, and 90% to 95% of penicillin-resistant S. pneumoniae.
• The first-line use of Cefdinir, cefpodoxime proxetil and cefuroxime axetil should be considered in patients with moderate-to-severe infections, and those with risk factors prompting a need for more effective antimicrobials.

TMP-SMX and erythromycin-sulfisoxazole acetyl
• These agents have lost efficacy against all major pathogens, including group A beta-hemolytic streptococci (GABHS).
• The sulfa component can cause hypersensitivity reactions.
• More than 90% of M. catarrhalis, more than 24% of H. influenzae, and more than 43% of S. pneumoniae are not susceptible to TMP-SMX.

Macrolides
• Erythromycin is inactive against H. influenzae and some Group A beta-hemolytic streptococci (GABHS).
• Resistance of GABHS to all the macrolides occurs in countries where these agents were overused.
• More than 35% of S. pneumoniae are resistant to all macrolides.
• Clarithromycin is more efficient than erythromycin against gram-positive organisms.
• Azithromycin (an azalide) has improved in vitro efficacy against gram-negative organisms (H. influenzae and M. catarrhalis).
• Azithromycin-susceptible H. influenzae can survive in the middle ear and sinuses.100,101 The persistence is explained by the accumulation of azithromycin within the middle ear or sinus endothelial cells only, and not in the middle ear or sinus fluid.

Clindamycin
• Good efficacy against aerobic gram-positive organisms, including approximately 90% of intermediately penicillin-resistant S. pneumoniae and up to 85% of methicillin-resistant S. aureus (MRSA)
• No activity against aerobic gram-negative pathogens ( including H. influenzae and M. catarrhalis) 98
• Effective against anaerobic bacteria

Quinolones (only in those > 18 years)
• Older quinolones (i.e., ciprofloxacin, ofloxacin)
a) Effective against H. influenzae and M. catarrhalis
b) Minimal activity against S. pneumoniae
c) Ciprofloxacin is the most effective quinolone against P. aeruginosa
• Newer (respiratory) quinolones (e.g., levofloxacin, and moxifloxacin)
a) Activity against S. pneumoniae, including penicillin-resistant isolates.
b) Good activity against gram-negative aerobic bacilli
• Moxifloxacin have greater in vitro activity than levofloxacin when tested against S. pneumoniae.
• These agents offer once-daily dosing and have low phototoxic potential.
• Moxifloxacin shows greater efficacy against anaerobes compared with the other quinolones.
• The first-line use of the “newer” fluoroquinolones should be considered in patients with moderate-to-severe infections, and those with risk factors prompting a need for more effective antimicrobials. Emerging reports of pneumococcal fluoroquinolone resistance underscore the need to curtail the inappropriate use of these drugs for infections that cannot be treated with beta-lactam antibiotics.

• Amoxicillin can be appropriate for the initial treatment of acute uncomplicated mild sinusitis. However, antimicrobials that are more effective against the major bacterial pathogens (including those that are resistant to multiple antibiotics) may be indicated as initial therapy and for the re-treatment of those who have risk factors prompting a need for more effective antimicrobials and those who had failed amoxicillin therapy.
•These agents include:
Amoxicillin and clavulanic acid
“newer” quinolones (e.g. levofloxacin, moxifloxacin)
Some 2nd & 3rd generation cephalosporins( cefdinir,cefuroxime-axetil,and cefpodoxime proxetil)

The guidelines for empirical therapy of acute sinusitis are:

Empirical antimicrobial therapy in acute bacterial sinusitis

Amoxicillin Therapy

Mild illness

No history of recurrent acute sinusitis

During summer months

When no recent antimicrobial therapy has been used

When patient has had no recent contact with patient(s) on antimicrobial therapy

When community experience shows high success rate of amoxicillin

Risk factors prompting a need for more effective antimicrobials*

Bacterial resistance is likely

Antibiotic use in the past month, or close contact with a treated individual(s)

* amoxicillin and clavulanic acid, 2nd and 3rd generation cephalosporins, and the “respiratory” quinolones (only in those > years old).

The recommended antimicrobial for initial treatment of acute sinusitis or after no improvement are:

Factors prompting more effective antibiotics*

At diagnosis

Clinically treatment failure at 48-72 hours after starting treatment

No

High-dose amoxicillin

High-dose amoxicillin/clavulanate or “new” quinolone

or cefuroxime

or cefdinir

or cefpodoxime proxetil

Yes

High-dose amoxicillin/clavulanate or “new” quinolone

or cefuroxime-axetil

or cefdinir

or cefpodoxime proxetil

High-dose amoxicillin/clavulanate or “new” quinolone

or cefuroxime-axetil

or cefdinir

or cefpodoxime proxetil

Because of increasing resistance to amoxicillin (the current standard of care) the Infectious Diseases Society of America (IDSA) 2012 guideline recommends amoxicillin-clavulanate as the treatment of choice of actute sinusitis. The guidelines also recommend against other commonly used antibiotics, including azithromycin, clarithromycin and trimethoprim/sulfamethoxazole, because of growing drug resistance.

• Several retrospective studies illustrate the superiority of antibiotic therapy effective against both aerobic and anaerobic BLPB in chronic bacterial sinusitis.
• Many of the anaerobes isolated from chronically inflamed sinuses, such as Bacteroides fragilis and more than one half of the Prevotella and Fusobacterium spp., resist penicillins through the production of beta-lactamase.
• Some of the aerobic isolates (S. aureus and H. influenzae) are also BLPB.
• Growing number of S. aureusare MRSA
• Antimicrobial agents used for chronic sinusitis therapy should be effective against aerobic and anaerobic BLPB.
a) These include agents available in oral and/or parenteral formulations: the combination of a penicillin (i.e., amoxicillin, ticarcillin) and a beta-lactamase inhibitor (i.e., clavulanic acid), clindamycin, and the combination of metronidazole and amoxicillin, a macrolide.
b) Other effective agents are available only in parenteral form (e.g., cefoxitin and the carbapenems).
c) If gram-negative organisms (e.g., P. aeruginosa) are involved, parenteral therapy with an aminoglycoside, a fourth-generation cephalosporin (cefepime or ceftazidime), or oral or parenteral treatment with ciprofloxacin should be given.
• Fungal bacterial sinusitis can be treated with surgical debridement and antifungal therapy.
• Antimicrobial therapy without surgical drainage of collected pus may not result in clearance of the infection. Surgical drainage should be considered when the patient does not respond to medical therapy. Impaired drainage can lead to chronic bacterial sinusitis, and relief of the obstruction helps to alleviate the infection and prevent recurrence.

The goal of antimicrobial therapy is eradication of susceptible organisms in the sinus. The growing resistance to antimicrobial agents of respiratory tract bacterial pathogens makes the management of bacterial sinusitis more difficult.

The main causes for failure of bacterial sinusitis treatment are viral infection, noncompliance, resistant organism, inadequate penetration of antibiotics to the sinuses, lack of drainage (anatomical blockage, or due to medication, persistence of predisposing risk factors, and impaired host defenses. If the patient fails to show significant improvement or shows signs of deterioration despite treatment, a culture should be obtained preferably through sinus puncture or endoscopy. This may reveal the causative bacteria and the presence of resistant bacteria. Further antimicrobial treatment is based, whenever possible, on results of the culture. Selection of the antimicrobial(s) is generally made on an empirical basis, and the agents chosen should be effective against the potential pathogens.

CAUSES OF ANTIMICROBIAL THERAPY FAILURE ARE:

Viral infection

Noncompliance

Resistant organism(s) as a result of:

Recent treatment with antibiotic agents

Acquisition of resistant organisms (community, day care, school, or nosocomial)

Emergence of resistance during therapy

Inadequate penetration of antibiotics to site

Lack of drainage (anatomical blockage, or due to medication)

Persistence of predisposing risk factors

Impaired host defenses

In the empirical choice of antimicrobial therapy for sinuses, several balances between narrow-spectrum and wide-spectrum antimicrobial agents must be made.
A narrow spectrum antibiotic effective against the pathogen is preferred whenever possible as it can eliminate the causative agents and preserve the normal endogenous bacterial flora with minimal selection of resistant bacteria.

Indications for the use of antimicrobial therapy should be strict, and they should generally be given only when bacterial sinus infection is present. In patients who are not toxic, the duration of symptoms can generally differentiate viral infections from bacterial sinusitis. In those with symptoms for more than 10 days, antimicrobials effective against the most prevalent pathogens should be administered.

The greater rate of recovery of MRSA in acute and chronic sinusitis mandates a greater index of suspicion for the presence of this organism in sinusitis and greater use of sinus cultures especially in patients who do not improve or fail antimicrobial after 48 hours of therapy to guide the proper selection of antimicrobials agents.

DURATION OF THERAPY

The length of therapy of acute sinusitis is 5 to 14 days. A short course of 5 day therapy for acute sinusitis is indicated for azithromycin. The IDSA 2012 guideline suggest five to seven days of antibiotics is long enough to treat a bacterial infection without encouraging resistance. The guideline still do recommend children receive antibiotic treatment for 10 days to two weeks.

• The recommended length of therapy for acute bacterial sinusitis is 5-14 days depending on the antimicrobial chosen and the patient condition.
• Therapy may be prolonged for up to a month if the symptoms improve without complete resolution.
• Reevaluation is recommended if no improvement is observed within 72 hours, and especially if the symptoms worsen. Changing the antimicrobial agent should be considered at this time, preferably based on culture results.

• The recommended length of antimicrobial therapy is 3 to 6 weeks.
• If improvement is not seen within 5 to 7 days, a culture is obtained and the antimicrobial agent changed.
• For patients who respond slowly, therapy is continued for an additional 2 to 4 weeks, depending on the rapidity of the response.
• Parenteral antibiotics may be considered in situations of poor compliance.
• These agents should be administered to patients where bacterial resistance is likely ( i.e. recent antibiotic therapy, winter season, increases resistance in the community), the presence of a moderate to severe infection, the presence of co-morbidity ( diabetes, chronic renal, hepatic or cardiac pathology), and when penicillin allergy is present.
• Agents that are less effective because of growing bacterial resistance may however be considered for patients with antimicrobial allergy. Thse include: the macrolides, TMP-SMX, tetracyclines, and clindamycin.

About Me

Dr. Itzhak Brook is a physician who specializes in pediatrics and infectious diseases.
He is a Professor of Pediatrics at Georgetown University Washington D.C. and his areas of expertise are anaerobic and head and neck infections including sinusitis. He has done extensive research on respiratory tract infections and infections following exposure to ionizing radiation. Dr. Brook served in the US Navy for 27 years. He is the author of six medical textbooks, 155 medical book chapters and many scientific publications. He is an editor of four and associate editor of four medical journals. He is a board member of the Head and Neck Cancer Alliance. Dr. Brook is the recipient of the 2012 J. Conley Medical Ethics Lectureship Award by the American Academy of Otolaryngology-Head and Neck Surgery.
Dr. Brook was diagnosed with throat cancer in 2006.

Disclaimer

This blog is not a substitute for medical care by medical professionals. Patients should consult with their personal physicians before making any decisions about their medical and surgical care. Physicians and other providers reading this blog should make independent, informed decisions about the care of their patients based on the individual facts and circumstances of each case.